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Vol. 54, Issue 2, 203-218, June 2002
Endocrine, Mucosal Inflammation, Smooth Muscle and Cancer Biology
Research Groups, Department of Pharmacology and Therapeutics and
Department of Medicine, University of Calgary, Faculty of Medicine,
Calgary, Alberta, Canada
I. Introduction
II. Nomenclature and Use of the Proteinase-Activated Receptor
Designation
III. Receptor Subtypes
A. Defining Proteinase-Activated Receptor Subtypes Using Enzyme and
Peptide Agonists
B. Receptor Antagonists and Receptor Subtypes
C. Molecular Definition of Receptor Subtypes
IV. Molecular Aspects of Proteinase-Activated Receptor Activation
A. The Tethered Ligand Mechanism
B. Structure-Activity Relationships for Receptor Activation by the
Tethered Ligand Sequences
C. Receptor Domains Involved in Ligand Activation
D. Signaling, Desensitization, and Receptor Internalization
E. Receptor Activation and Proteinase Susceptibility: What Are the
Endogenous Proteinase-Activated Receptor Regulators?
V. Physiological Roles of Proteinase-Activated Receptors
A. Thrombin Targets: Proteinase-Activated Receptors 1, 3, and 4
B. Proteinase-Activated Receptor 2, a Trypsin Target
VI. Future Issues and Conclusions
Acknowledgments
References
Proteinase-activated receptors (PARs) represent a unique subclass of G-protein-coupled receptors of which four family members have now been cloned from a number of species. The novel mechanism of receptor activation involves the proteolytic unmasking of a cryptic N-terminal receptor sequence that, remaining tethered, binds to and triggers receptor function. In addition, short (five to six amino acids) synthetic peptides, based on the proteolytically revealed motif, can activate PARs without the unmasking of the tethered ligand. This article summarizes the experiments leading to the pharmacological characterization and cloning of the four PAR family members and provides a rationale for their designation by the acronym "PAR". The ability to distinguish among the PARs pharmacologically 1) with selective proteinase activators, 2) with receptor-selective peptide agonists, and 3) with peptide and nonpeptide antagonists is discussed, as are the molecular mechanisms of receptor activation and desensitization/internalization. Finally, the potential physiological roles of the PARs, which are widely distributed in many organs in the settings of tissue injury, repair, and remodeling, including embryogenesis and oncogenesis are discussed, and the newly appreciated roles of proteinases as signaling molecules that can act as either functional agonists or antagonists are highlighted.
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J. J. McGuire, M. Saifeddine, C. R. Triggle, K. Sun, and M. D. Hollenberg 2-Furoyl-LIGRLO-amide: A Potent and Selective Proteinase-Activated Receptor 2 Agonist J. Pharmacol. Exp. Ther., June 1, 2004; 309(3): 1124 - 1131. [Abstract] [Full Text] [PDF]
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D. Darmoul, V. Gratio, H. Devaud, and M. Laburthe Protease-activated Receptor 2 in Colon Cancer: TRYPSIN-INDUCED MAPK PHOSPHORYLATION AND CELL PROLIFERATION ARE MEDIATED BY EPIDERMAL GROWTH FACTOR RECEPTOR TRANSACTIVATION J. Biol. Chem., May 14, 2004; 279(20): 20927 - 20934. [Abstract] [Full Text] [PDF]
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 Y. Dai, T. Moriyama, T. Higashi, K. Togashi, K. Kobayashi, H. Yamanaka, M. Tominaga, and K. Noguchi Proteinase-Activated Receptor 2-Mediated Potentiation of Transient Receptor Potential Vanilloid Subfamily 1 Activity Reveals a Mechanism for Proteinase-Induced Inflammatory Pain J. Neurosci., May 5, 2004; 24(18): 4293 - 4299. [Abstract] [Full Text] [PDF]
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A. Garcia, S. Prabhakar, S. Hughan, T. W. Anderson, C. J. Brock, A. C. Pearce, R. A. Dwek, S. P. Watson, H. F. Hebestreit, and N. Zitzmann Differential proteome analysis of TRAP-activated platelets: involvement of DOK-2 and phosphorylation of RGS proteins Blood, March 15, 2004; 103(6): 2088 - 2095. [Abstract] [Full Text] [PDF]
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B. Al-Ani, K. K. Hansen, and M. D. Hollenberg Proteinase-Activated Receptor-2: Key Role of Amino-Terminal Dipeptide Residues of the Tethered Ligand for Receptor Activation Mol. Pharmacol., January 1, 2004; 65(1): 149 - 156. [Abstract] [Full Text] [PDF]
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 Y. V. Kim, F. Di Cello, C. S. Hillaire, and K. S. Kim Differential Ca2+ signaling by thrombin and protease-activated receptor-1-activating peptide in human brain microvascular endothelial cells Am J Physiol Cell Physiol, January 1, 2004; 286(1): C31 - C42. [Abstract] [Full Text] [PDF]
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J. Trejo Protease-Activated Receptors: New Concepts in Regulation of G Protein-Coupled Receptor Signaling and Trafficking J. Pharmacol. Exp. Ther., November 1, 2003; 307(2): 437 - 442. [Abstract] [Full Text] [PDF]
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C. E. Junge, T. Sugawara, G. Mannaioni, S. Alagarsamy, P. J. Conn, D. J. Brat, P. H. Chan, and S. F. Traynelis The contribution of protease-activated receptor 1 to neuronal damage caused by transient focal cerebral ischemia PNAS, October 28, 2003; 100(22): 13019 - 13024. [Abstract] [Full Text] [PDF]
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P. J. O'Brien, H. Koi, S. Parry, L. F. Brass, J. F. Strauss III, L.-P. Wang, J. E. Tomaszewski, and L. K. Christenson Thrombin Receptors and Protease-Activated Receptor-2 in Human Placentation: Receptor Activation Mediates Extravillous Trophoblast Invasion in Vitro Am. J. Pathol., October 1, 2003; 163(4): 1245 - 1254. [Abstract] [Full Text] [PDF]
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A. C. Chin, N. Vergnolle, W. K. MacNaughton, J. L. Wallace, M. D. Hollenberg, and A. G. Buret Proteinase-activated receptor 1 activation induces epithelial apoptosis and increases intestinal permeability PNAS, September 16, 2003; 100(19): 11104 - 11109. [Abstract] [Full Text] [PDF]
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Y. Gui, R. Loutzenhiser, and M. D. Hollenberg Bidirectional regulation of renal hemodynamics by activation of PAR1 and PAR2 in isolated perfused rat kidney Am J Physiol Renal Physiol, July 1, 2003; 285(1): F95 - F104. [Abstract] [Full Text] [PDF]
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D. Darmoul, V. Gratio, H. Devaud, T. Lehy, and M. Laburthe Aberrant Expression and Activation of the Thrombin Receptor Protease-Activated Receptor-1 Induces Cell Proliferation and Motility in Human Colon Cancer Cells Am. J. Pathol., May 1, 2003; 162(5): 1503 - 1513. [Abstract] [Full Text] [PDF]
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B. Al-Ani and M. D. Hollenberg Selective Tryptic Cleavage at the Tethered Ligand Site of the Amino Terminal Domain of Proteinase-Activated Receptor-2 in Intact Cells J. Pharmacol. Exp. Ther., March 1, 2003; 304(3): 1120 - 1128. [Abstract] [Full Text] [PDF]
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M. R. D'Andrea, M. R. Saban, N.-B. Nguyen, P. Andrade-Gordon, and R. Saban Expression of Protease-Activated Receptor-1, -2, -3, and -4 in Control and Experimentally Inflamed Mouse Bladder Am. J. Pathol., March 1, 2003; 162(3): 907 - 923. [Abstract] [Full Text] [PDF]
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L. A. Boven, N. Vergnolle, S. D. Henry, C. Silva, Y. Imai, J. Holden, K. Warren, M. D. Hollenberg, and C. Power Up-Regulation of Proteinase-Activated Receptor 1 Expression in Astrocytes During HIV Encephalitis J. Immunol., March 1, 2003; 170(5): 2638 - 2646. [Abstract] [Full Text] [PDF]
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J. J. McGuire, J. Dai, P. Andrade-Gordon, C. R. Triggle, and M. D. Hollenberg Proteinase-Activated Receptor-2 (PAR2): Vascular Effects of a PAR2-Derived Activating Peptide via a Receptor Different than PAR2 J. Pharmacol. Exp. Ther., December 1, 2002; 303(3): 985 - 992. [Abstract] [Full Text] [PDF]
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M. D. Hollenberg PARs in the stars: proteinase-activated receptors and astrocyte function. Focus on "Thrombin (PAR-1)-induced proliferation in astrocytes via MAPK involves multiple signaling pathways" Am J Physiol Cell Physiol, November 1, 2002; 283(5): C1347 - C1350. [Full Text] [PDF]
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